Alcohol free formulation of argatroban

ABSTRACT

An aqueous formulation of argatroban and of related compounds is disclosed along with a reconstitutable formulation, each of which is substantially, if not totally alcohol free. The formulations are also substantially free, if not totally free, of mono-, di-, and oligo-saccharides. An especially preferred embodiment is a ready-to-administer 1 mg/ml injectable dosage form having argatroban, lactobionic acid, and methionine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of a U.S. application Ser.No. 11/904,067, filed Sep. 26, 2007, which claims priority of U.S.Provisional Application Ser. No. 60,850,725, filed Oct. 11, 2006 andU.S. Provisional Application Ser. No. 60/847,556, filed Sep. 27, 2006.This Application also claims priority directly from U.S. ProvisionalApplication Ser. No. 60/850,725, filed Oct. 11, 2006. Reference is alsomade to co-owned PCT/US07/20725, filed Sep. 26, 2007 having the sametitle and inventorship as the instant application and claiming priorityfrom the same two provisional applications above and to co-owned PCTapplication filed concurrently herewith having the same inventorship andtitle as the present application and is a Continuation-in-partPCT/US2007/020725, filed Sep. 26, 2007. Each of these applications aswell as each patent and patent application mentioned in the rest of thisspecification is incorporated herein by reference in their entireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable

FIELD OF THE INVENTION

The present invention relates to argatroban and to the solubilizationthereof to yield injectable and other aqueous solutions of desiredconcentration in aqueous media without the need for alcohols or othersolvents and without the use of saccharides.

BACKGROUND OF THE INVENTION

Argininesulfonamides are known to have anti-thrombotic activities (seee.g., Japanese Patent No. 1382377). However, it is very difficult toobtain a solution containing any of the argininesulfonamides at highconcentrations due to their general poor solubility in water. Thereforethese compounds are generally not suitable for use in injectionformulations containing them at high concentrations. U.S. Pat. No.5,214,052 attempts to solve this problem by dissolving these compoundsin a dissolution media containing water, ethanol, and a saccharide(inclusive of monosaccharides, disaccharides, oligosaccharides and theirreduced sugar alcohol counterparts). Argatroban, currently marketed byEncysive in the U.S., is sold as a 2.5 ml vial of 100 mg/ml argatrobanconcentrate having 750 mg D-sorbitol, and 1000 mg dehydrated alcohol perml, which concentrate is subsequently diluted to 1 mg/ml argatroban foractual use. While that formulation allows for advantages in packagingand dissolution to final concentration, it suffers from the drawback ofhaving ethanol present in a not insignificant amount, especially whenthe patient in question is of smaller body weight. Currentadministration rates include 6 ml/hr (of the 1 mg/ml diluted solution)for a 50 kg patient to 17 ml/hr (of the 1 mg/ml diluted solution) for a140 kg patient each for the duration of the procedure for whichargatroban administration is desired. Thus, each vial supplied provides250 ml of administrable diluted solution, resulting in substantial wasteof material in all but the most prolonged procedures (250 ml beingsufficient for over 40 hours for a 50 kg patient and over 14 hours for a140 kg patient).

OBJECT OF THE INVENTION

An object of the invention is to provide a method for improving thesolubility of argatroban in a completely aqueous system, in particularavoiding the use of organic solvents such as monoalcohols of 1-4 carbonatoms, especially ethanol, and still obtain solutions of sufficientconcentration for use in parenteral administration.

A further object of the invention is to provide an argatrobanformulation that is substantially free of saccharides, inclusive ofmono-saccharides, di-saccharides, oligosaccharides, and theircorresponding sugar alcohols.

Another object of the invention is to provide a dosage form ofargatroban that is not as concentrated so that further dilution for usedoes not result in substantial waste of material in most typicaladministration settings.

A further object of the invention is to provide a dosage form ofargatroban not requiring an extensively large dilution, yet beconcentrated sufficiently to be convenient for preparing for use andless subject to dissolution errors than with current marketedargatroban.

Still a further object of the invention is to provide 1 mg/mlready-to-administer solutions of argatroban in 5 ml to 500 ml vials and25 ml to 500 ml infusion bags.

Yet another object of the invention is to provide an argatrobanready-to-administer formulation having a storage stability of at leastabout 18 months.

Still another object of the invention is to provide an argatrobanready-to-administer formulation having a substantial stability withrespect to pH in a terminal sterilization operation.

An even further object of the invention is to provide an argatrobanready-to-administer formulation having a substantial stability withrespect to degradation product in a terminal sterilization operation.

An even further object of the invention is to provide an argatrobanready-to-administer formulation having a substantial stability withrespect to degradation product in the presence of an antioxidizing agentsuch as methionine in an aseptic operation or in a terminalsterilization operation.

Still another object of the invention is the use of lactobionic acid asa solubilizer and/or stabilizer to enhance the aqueous solubility aswell as stability of argatroban.

Yet another object of the invention is to provide an argatrobanready-to-administer aqueous solution for injection having carbonateand/or bicarbonate ion present.

Yet further objects of the invention will be apparent to those ofordinary skill in the art.

SUMMARY OF THE INVENTION

The invention provides a method for dissolving argatroban comprisingdissolving argatroban or a pharmaceutically acceptable salt thereof inan aqueous, preferably buffered, system that is substantially free oflower alcohols and is substantially free of saccharides (e.g., mono-,di-, and oligo-saccharides and their corresponding sugar alcohols).Further, the invention provides pharmaceutical compositions containingargatroban.

DETAILED DESCRIPTION OF THE INVENTION

In certain embodiments, the invention provides a method for dissolvingargatroban comprising dissolving an N²-arylsulfonyl-L-arginine havinggeneral formula (I) or a pharmaceutically acceptable salt thereof

The compound exists as optical isomers and for purposes of thisapplication, reference to “argatroban” (unless indicated or the contextrequires otherwise) refers to the individual isomers as well as thevarious mixtures of isomers in various proportions. Currently marketedargatroban has the chemical name set forth in its labeling as(2R,4R)-1-[N²-(3-methyl-1,2,3,4-tetrahydro-8-quinoline-sulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylicacid. Further, unless indicated otherwise or the context requiresotherwise, reference to “argatroban” includes reference to the variouspharmaceutically acceptable salts thereof, whether salts thereof withacids or bases.

The invention can use the pharmaceutically acceptable salts ofargatroban. The salts may be acid addition salts (there being a freecarboxy group present) prepared by reacting the argatroban or adifferent salt thereof (inclusive of (a) pharmaceutically acceptablesalts other than the salt being made and (b) pharmaceuticallyunacceptable salts) with any pharmaceutically acceptable inorganic ororganic acid such as, without limitation, hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid,carbonic acid, acetic acid, citric acid, maleic acid, succinic acid,lactic acid, tartaric acid, gluconic acid, glucuronic acid, ethers ofglucuronic acid or gluconic acid (such as lactobionic acid), benzoicacid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acidand p-toluenesulfonic acid. Further, the salts may be inorganic ororganic salts prepared by reacting the argininesulfonamide of generalformula (I) with any pharmaceutically acceptable organic or inorganicbases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide,sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassiumcarbonate, ammonium bicarbonate, ammonium carbonate, triethylamine,procaine, dibenzylamine, N,N′-dibenzylethylenediamine andN-ethylpiperidine.

In one method for dissolving argatroban according to the invention, theargatroban and/or its salt is dissolved in an amino acid aqueoussolution. The amino acid used in the invention is preferably selectedfrom arginine, glycine, methionine, or other amino acids with at leastone basic group pKa >9.0 or mixtures thereof. The amino acid can be usedas the acid or a salt thereof or mixtures thereof. While either D- or L-or D,L-amino acids can be used, L-amino acids are generally preferred inthis first embodiment. In another embodiment, discussed below, D,L-aminoacids are generally preferred. The pH of the drug and amino acidsolution is adjusted to about 8.0 to about 10.0 with one or morepharmaceutically acceptable carboxylic acids such as, withoutlimitation, acetic acid or any other carboxylic acid or dicarboxylicacid or hydroxy carboxylic acid; and may be adjusted with either theacid itself, or a salt thereof, or mixtures thereof if an appropriate pHcan be reached using such salt or mixture of salt and acid. More highlypreferred amino acids are arginine, glycine, and methionine. In thisfirst embodiment, arginine and glycine are even more highly preferred,while in a second embodiment discussed more specifically below,methionine is an even more highly preferred amino acid. The amino acid,when having buffering capacity in the desired region, can beself-buffering so that a separate buffer is not required; in this casepH adjustment can be accomplished with inorganic acids and bases (e.g.,HCl or NaOH, among others). In addition to the monocarboxylic aminoacids such as arginine, glycine, and methionine, among others, the aminoacid may be a dicarboxylic amino acid selected from formulas II and III

where A and B are each independently selected from (a) a branched orunbranched alkyl of 0-6 carbons, provided that the sum of the carbonatoms in A and B do not exceed 6; (b) a branched or unbranchedheteroalkyl having up to 2 heteroatoms selected from N and O, providedthat the sum of the carbon and heteroatoms in A and B do not exceed 6;(c) 5-6 membered cycloalkyl, 5-6 membered heteroalkyl having up to 2heteroatoms selected form N, O, and S; (d) 6 membered aryl or heteroarylhaving up to 2 hetero atoms selected from N, O, and S; preferablydicarboxylic amino acids of formula II are those where A and B are bothlimited to alkyls of 0-6 carbons, more preferably those where the aminogroup is in an alpha or beta position to at least one of the carboxylicgroups, and even more preferably where the two carboxylic acid groupsare separated by at least 2 carbon atoms.

where ring C is a six-membered aromatic or heteroaromatic ring orpartially or fully saturated analog thereof, having up to 2 heteroatomsselected from N, O, and S and on which the amino and the carboxylic acidgroups can be present at any available position of such ring C, and eachn is independently an interger of 0-3, preferably each n is zero.Exemplary dicarboxylic amino acid of formula II are, without limitation,glutamic acid and aspartic acid. An exemplary amino acid with formulaIII is amino phthalic acid. In all of the amino acids for the presentinvention, the pKa of the basic function (or of at least one basicfunction if more than one is present) should be greater than about 9.

In the present invention, reference to a given weight of a compound thatcan exist as a salt or in free form is with reference to the free formof the compound. Thus, for a compound such as argatroban having amolecular weight of 526 g, and monosodium argatroban having a molecularweight of 548 Dalton, and argatroban monohydrochloride having amolecular weight of 561 Dalton, an indication of “52.6 mg of argatroban”will mean 52.6 mg of argatroban non-salt form, or if the monosodium saltis being discussed, 52.6 mg of argatroban will mean 54.8 mg ofmonosodium argatroban having 52.6 mg of the argatroban moiety present,or if the argatroban monohydrochlodride is being discussed, it will mean56.1 mg of argatroban monohydrochloride having 52.6 mg of the argatrobannon-salt moiety present. Corresponding calculations to find the exactweight of the salt form under discussion for other salts are known tothose of ordinary skill in the art. Weights of amino acids will also bereferenced to the non-salt forms thereof with appropriate calculationsto find the precise weight of a particular salt being known to those ofordinary skill in the art.

The amino acid is generally present in amounts that are about 1.5 toabout 2.5, preferably about 2 times the amount of the compound offormula (I) present (based on the non-salt form of argatroban). Whenpresent, the carboxylic acid (other than carbonic acid salt) isgenerally present in amounts that are about 1.5 to about 2.5, preferablyabout 2 times the amount of argatroban present (based on the argatrobanmoiety), while (when present) the carbonic acid salt is generallypresent in an amount of about 1.4 to about 5.2 (based on CO₃ content)times the amount of argatroban present (based on the argatroban moiety),preferably about 1.5 to about 2.5 times, more preferably about 1.9 toabout 2.0 times when the amino acid is absent and preferably about 3.0to about 5.2 times, more preferably about 4.1 to about 4.2 times whenthe amino acid is present. Those of ordinary skill in the art will beable to adjust these amounts for the situation where both a carboxylicacid (other than carbonic acid salt) is present in combination with acarbonic acid salt.

Water as used in the present invention (unless indicated otherwise orthe context requires otherwise) includes aqueous injectable fluidsincluding, but not limited to, distilled water, purified water, waterfor injection, a physiological saline, Ringer's Solution, LactatedRinger's Solution and 5% dextrose solution, and any of these may be usedfor diluting concentrates. Preferably in preparing theready-to-administer formulations, distilled water, purified water orwater for injection is used with a post formulation sterilizationprocedure, or preferably water for injection is used if post-formulationsterilization is not being used.

The manner of how to dissolve the argatroban in water and optionally inan amino acid aqueous solution is not particularly limited. Generally,the amino acid (or its salt or a mixture of the amino acid and itssalt), when present, is dissolved in water and then the pH is adjustedupward, if need be, to about pH 8.7 to about 10 with the addition ofinorganic or organic base (or salts of carboxylic acid or mixtures ofits salts and their conjugate acids or conjugate bases (inclusive ofalkali metal salt(s) and ammonium salts of carbonic acid)) theretofollowed by mixing. These two steps can be reversed if desired. Next,the argatroban is slowly added while stirring until completedissolution. If desired, but not required, the pH can then be adjusteddownward using any suitable inorganic or organic acid or buffer thereof.Where concentrates are to be made for subsequent dilution, higher pH canbe tolerated for the dissolution and storage phase as the subsequentdilution will bring the pH closer to physiologic pH before injection.Concentrates having the amino acid in the range of 50 mg/ml (especiallywhen using arginine as the amino acid) will have a pH as high as about11 to about 11.5 before addition of the argatroban. In theseconcentrates, the argatroban is dissolved and the pH is adjusteddownward into the range of about 8.7 to 9.5 as discussed above using anappropriate acid or buffer. Where a ready-to-administer injectionformulation is desired, the ready-to-administer product pH shouldgenerally not be greater than about pH about 9.5, preferably not greaterthan about 9.2, and more preferably is usually about pH 8.7, about 8.8,about 8.9, about 9.0, about 9.1, or about 9.2. Certain advantageousready to use formulations of the present invention have a pH of about8.7, while certain other advantageous ready-to-use formulations of thepresent invention have a pH of about 9.2.

The temperature on dissolution is not particularly limited. When theargatroban is dissolved in water, however, it is preferable to warm thewater to about 40° C. to about 80° C. for accelerating the dissolutionrate, about 70° C. being advantageous in a number of situations.

The concentration of argatroban in the solution can be selected within awide range depending on the intended uses. According to the invention,the solution in which the argatroban is dissolved may result inconcentrations of argatroban that are several fold higher than theconcentrations of argatroban typically obtained with the solubility ofargatroban in water alone. Most advantageously for one embodiment of theconcentrates of the present invention, the argatroban can be dissolvedup to about 7.5 mg/ml, preferably about 6 mg/ml, most preferably about 5mg/ml. An additional embodiment within the invention is aready-to-administer solution of about 0.8 to about 1.25 mg/ml,preferably about 0.9 to about 1.1 mg/ml, more preferably about 1 mg/mlargatroban. All amounts presented are amounts of argatroban freecompound that is the non-salt. Corresponding amounts of various saltswill be readily known to those of ordinary skill in the art by routinecalculation.

In a second embodiment of the invention, the argatroban, or apharmaceutically acceptable salt thereof, is dissolved in an aqueoussolution of a gluconic or glucuronic acid (or a sugar ether of either,where the sugar position 1 is etherified with one of the hydroxyl groupsof the gluconic or glucuronic acid, preferably the ether is lactobionicacid or a salt thereof) and/or with an alkali metal (e.g., sodium orpotassium) or ammonium salt, preferably a sodium salt, of carbonic acid(e.g., sodium carbonate, sodium bicarbonate, and mixtures thereof) andoptionally an amino acid or salt thereof. In each case, the salts, ifpresent are pharmaceutically acceptable salts, and in the case of use ofthe solution as an injectable, the salt is compatible with its use in aninjectable formulation. Preferably, the formulation comprises argatrobanor a pharmaceutically acceptable salt thereof; a gluconic acid orglucuronic acid, or an ether of either or a pharmaceutically acceptablesalt thereof (preferably lactobionic acid or a pharmaceuticallyacceptable salt thereof) and/or an alkali metal or ammonium salt ofcarbonic acid, preferably a sodium salt of carbonic acid or mixture ofsodium salts of carbonic acid; optionally an amino acid, preferably ananti-oxidant amino acid (more preferably methionine), arginine, orglycine, either in the D-, L-, or D,L-form, preferably as the D,L-form,the amino acid optionally in the form of a pharmaceutically acceptablesalt thereof; and water (which water may further contain an optionalinert osmolarity adjuster (other than a saccharide) so as to bring thesolution to an appropriate osmolarity if desired); and wherein theformulation is substantially free of ethanol, preferably beingsubstantially free of at least one of if not both of (a) monohydricalcohols having 1 to 4 carbons; and (b) mono-, di-, and oligosaccharidesand their corresponding sugar alcohols. For the present invention,“substantial free” when referring to a lower alcohol means less thanabout 5% v/v, preferably less than about 2.5%, more preferably less thanabout 1%, more preferably less than about 0.5% v/v; while when referringto “saccharide” means less than about 10% w/v, preferably less thanabout 7.5%, more preferably less than about 5%, still more preferablyless than about 2.5%, even more preferably less than about 1%, yet morepreferably less than about 0.05% w/v. Formulations having the requiredcomponents and either or both lower alcohols and saccharides (inclusiveof mono-, di- and oligo-saccharides and their corresponding sugaralcohols) are within the present invention, should one so desire, butthe emphasis of the invention is primarily on the avoidance of the loweralcohol or saccharide and particularly the avoidance of both. Inclusionof methionine or another anti-oxidant amino acid improves the productstability especially with respect to terminal sterilization, and istherefore one particularly preferred embodiment.

In this embodiment, it is preferable to first heat the water, preferablyto boiling, then allow the water to cool to a temperature of about30-50° C., preferably about 35° C. The carboxylic acid (preferablylactobionic acid or pharmaceutically acceptable salt thereof and/oralkali metal or ammonium salt of carbonic acid) is added and dissolved.Then, any optional amino acid is added and dissolved. Then theargatroban (or a pharmaceutically acceptable salt thereof) is added anddissolved. In this procedure, the amino acid and carboxylic acidaddition steps can be reversed, if desired, or the amino acid can beadded after the argatroban. The pH is adjusted as convenient at anypoint prior to the addition of the compound of formula (I) orpharmaceutically acceptable salt thereof to a pH in excess of about 8.5,preferably in excess of about 8.6, more preferably to about pH 8.7 toabout 9.5, more particularly about pH 8.7 to about 9.2, still morepreferably about 8.7, about 8.8, about 8.9, about 9.0, about 9.1 orabout 9.2, so as to aid in the dissolution of the compound of formula(I).

Higher pH's are acceptable for the dissolution phase for concentrateformulations that will be further diluted before actual injection,provided the dilution brings down the pH to a range such that upondilution to the final use concentration the pH is physiologicallyacceptable for injection purposes, typically less than about 9.5,generally less than about 9.2, preferably less than about 9.0, morepreferably less than about 8.8, still more preferably about 8.7; dilutedpH of about 8.6, about 8.7, about 8.8, about 8.9, about 9.0, about 9.1,and about 9.2 are all acceptable if so desired. If need be, finaladjustment of pH can be made with an acid or base or buffer asappropriate such as among others hydrochloric acid, sodium hydroxide, ora buffer solution of either or both the carboxylic acid/carboxylic acidsalt (inclusive of blends of alkali metal or ammonium salts of carbonicacid) and/or the amino acid/amino acid salt. Thus, a concentrateformulation may be prepared within the instant invention which has asubstantially high pH, while the ready-to-administer formulations willhave a generally weakly alkaline pH, generally greater than about 8.6and generally less than about 9.2.

The solution thus obtained containing the argatroban, amino acid, waterand carboxylic acid constitutes a first embodiment of the pharmaceuticalcomposition of the invention, while the solution containing (a) theargatroban; (b) water; (c) (1) gluconic acid, glucuronic acid, and/orether thereof, and/or (c) (2) an alkali metal or ammonium salt ormixtures of alkali metal or ammonium salts of carbonic acid; and (d)optional (preferably anti-oxidant) amino acid constitutes a secondembodiment, and the solution containing the argatroban, amino acid, andwater with or without the carboxylic acids constitutes a thirdembodiment of the invention. As will be readily recognized, embodimentsone and two overlap when the carboxylic acid in the first embodiment isselected from gluconic acid, glucuronic acid, the ether of either(especially lactobionic acid) and alkali metal salt or mixture of alkalimetal salts of carbonic acid; and the amino acid in the first embodimentis an anti-oxidant amino acid.

The pharmaceutical compositions of the invention are useful for treatingthrombosis and for treating and/or prophylaxis of any other conditionfor which the active agents are already known to be useful. Accordingly,the pharmaceutical compositions can be used as anti-thrombotic agents.

The pharmaceutical composition of the invention may contain antiseptic,anti-oxidant, soothing agents and the like. If necessary, anypharmaceutical ingredient(s) other than the argatroban may be added toform a combined preparation, provided such other ingredient is notunacceptable for the indication and route of administration; however,the invention compositions and processes are generally substantiallyfree of, if not totally free of (1) ethyl alcohol, more preferably anylower alcohol of 1-4 carbon atoms or (2) a saccharide, preferably amonosaccharide or disaccharide or oligo-saccharide, more preferably anysaccharide (wherein saccharide herein optionally includes the reducedsugar alcohol counterparts thereto), or (3) both (1) and (2). Whileformulations within the invention may contain either or both of thealcohols or saccharides (in more than insignificant amounts, they arepreferably substantially free, more preferably totally free of one orboth of these materials as stated earlier.

The primary composition of the invention in the first embodiment is apharmaceutical injectable and is administered as an injection. Thisinjectable composition may further contain stabilizer, buffer,preservative and the like that are acceptable for injection. If desired,the injectable composition according to the invention is prepared tocontain argatroban at a high concentration, which is used by dilutingwith water, electrolyte (e.g., normal saline, among others),carbohydrate solution (e.g., 5% Dextrose), Ringer's solution or the likeat or close to the time of administration (such as by infusion and/ordialysis). The concentrated formulation may contain amounts of up toabout 7.5 mg argatroban moiety, preferably up to about 5 mg per ml. Thisis generally diluted for administration to about 1 mg argatroban moietyper ml. Dilution of the concentrate to other concentrations for use asan injection will be within the ordinary skill in the art. Theformulation, as detailed further below, can also be prepared as alyophilizate or as a sterile dry fill product that can be reconstitutedwith appropriate diluent to either the concentrate concentrations ofthis embodiment or to the ready-to-use concentrations in the secondembodiment.

The primary composition of the invention second embodiment is also as apharmaceutically acceptable injection formulation, primarily as aready-to-administer composition. In this embodiment, the argatrobanmoiety is present in a concentration of no more than about 1.25 mg/ml,preferably about 1.1 mg/ml, more preferably about 1 mg/ml, in a pH ofabout 8.5 to about 9.2, preferably about 8.6 to about 8.9, morepreferably about pH 8.7 to about 8.9 in a water solution containing (a)as a carboxylic acid, at least one member selected from (1) gluconicacid, glucuronic acid, and sugar ethers thereof, especially lactobionicacid and pharmaceutically acceptable salts thereof and/or (2) alkalimetal or ammonium salt or mixture of alkali metal or ammonium salts ofcarbonic acid, and optionally (b) at least one (preferably anti-oxidant)amino acid or pharmaceutically acceptable salt thereof. If the freeargatroban concentration is greater than about 1.0 mg/ml, theconcentrate can be diluted with sufficient water of a suitable pH, withor without the amino acid or the carboxylic acid. In embodiments inwhich an osmotic adjuster material is utilized (other than as part ofdilution at the point of administration), the osmotic adjuster is anyinjectably suitable osmotic adjuster but preferably is not a saccharideor sugar alcohol, especially when an alcohol of 1-4 carbon atoms ispresent in the formulation.

EXAMPLES

The invention will now be further described by the following,non-limiting examples.

Example 1

(2R,4R)—1-[N²-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylicacid (argatroban) was dissolved (to a concentration of 5 mg/ml) in anaqueous system containing 50 mg/ml arginine with pH of the finalsolution adjusted to 9.2 with acetic acid. The dissolution of argatrobanwas carried out at 25° C.

Example 2

Argatroban is dissolved (to a concentration of 5 mg/ml) in an aqueoussystem containing 50 mg/ml arginine with pH adjusted to 9.0 with aceticacid. The dissolution of argatroban is carried out at 50° C.

Example 3

Argatroban is dissolved (to a concentration of 5 mg/ml) in an aqueoussystem containing 50 mg/ml arginine with pH adjusted to 9.0 withtartaric acid. The dissolution of argatroban is carried out at 25° C.

Example 4

Argatroban is dissolved (to a concentration of 5 mg/ml) in an aqueoussystem containing 50 mg/ml arginine with pH adjusted to 9.0 with citricacid. The dissolution of argatroban is carried out at 25° C.

Example 5

Argatroban is dissolved (to a concentration of 5 mg/ml) in an aqueoussystem containing 50 mg/ml arginine with pH adjusted to 9.0 with adipicacid. The dissolution of argatroban is carried out at 25° C.

Example 6

Argatroban is dissolved (to a concentration of 5 mg/ml) in an aqueoussystem containing 50 mg/ml lysine with pH adjusted to 9.0 with aceticacid. The dissolution of argatroban is carried out at 25° C.

Example 7

Argatroban is dissolved (to a concentration of 5 mg/ml) in an aqueoussystem containing 50 mg/ml arginine with pH adjusted to 10.0 with aceticacid. The dissolution of argatroban is carried out at 25° C.

Example 8

Argatroban is dissolved (to a concentration of 5 mg/ml) in an aqueoussystem containing 50 mg/ml arginine with pH adjusted to 8.0 with aceticacid. The dissolution of argatroban is carried out at 25° C.

Example 9

Examples 1-8 are repeated except that the dissolution is carried out atthe following concentrations (based on argatroban non-salt form) usingthe temperatures and form of argatroban as indicated:

Concentration of argatroban Form moiety Temperature Non-salt 5 mg/ml 15°C. Non-salt 5 mg/ml 20° C. Non-salt 5 mg/ml 30° C. Non-salt 5 mg/ml 35°C. Non-salt 7.5 mg/ml 15° C. Non-salt 7.5 mg/ml 20° C. Non-salt 7.5mg/ml 30° C. Non-salt 7.5 mg/ml 35° C. Sodium Salt 5 mg/ml 15° C. SodiumSalt 5 mg/ml 20° C. Sodium Salt 5 mg/ml 25° C. Sodium Salt 5 mg/ml 30°C. Sodium Salt 5 mg/ml 35° C. Sodium Salt 7.5 mg/ml 15° C. Sodium Salt7.5 mg/ml 20° C. Sodium Salt 7.5 mg/ml 25° C. Sodium Salt 7.5 mg/ml 30°C. Sodium Salt 7.5 mg/ml 35° C. Hydrochloride salt 5 mg/ml 15° C.Hydrochloride salt 5 mg/ml 20° C. Hydrochloride salt 5 mg/ml 25° C.Hydrochloride salt 5 mg/ml 30° C. Hydrochloride salt 5 mg/ml 35° C.Hydrochloride salt 7.5 mg/ml 15° C. Hydrochloride salt 7.5 mg/ml 20° C.Hydrochloride salt 7.5 mg/ml 25° C. Hydrochloride salt 7.5 mg/ml 30° C.Hydrochloride salt 7.5 mg/ml 35° C.

Example 10

6 vials of 5 mg/ml argatroban solution of Example 1 are diluted to 1mg/ml for a total of 30 ml of 1 mg/ml solution and used to administerthe same to a 50 kg patient at the rate of 6 mg/hour for a procedureexpected to be 4.5 hours. Upon completion of the procedure, there is aminimal amount of unused drug (less than 5 mg) as compared with over 200mg that would result from the currently marketed argatroban 100 mg/ml2.5 ml vials.

Attempts to use partial vials of the currently marketed 100 mg/ml 2.5 mlvial to dilute only 30 mg (0.3 ml) yield variations in actual amountswithdrawn for subsequent dilution and are thus not as reliable as usingcomplete 5 mg/ml vials of the present invention.

Example 11

Water is heated to boiling and allowed to cool to about 35° C.Lactobionic acid is added thereto in an amount to achieve aconcentration of about 2 mg/ml. Agatroban is then added thereto in anamount sufficient to achieve a concentration of about 1 mg/ml. Thesolution is packaged in appropriate containers as a ready-to useinjectable and the completed packages are terminally heat sterilized.

Example 12

Example 11 is repeated except that the solution pH is adjusted to about8.7 after addition of the lactobionic acid, but before the addition ofthe argatroban.

Example 13

Example 11 is repeated except that the amounts of lactobionic acid andargatroban are increased by an additional 10% and after the argatrobanhas been dissolved, optionally additional water at pH about 8.7 is addedto bring the final concentration of argatroban to about 1 mg/ml and thefinal concentration of lactobionic acid to about 2 mg/ml.

Examples 14

Water was heated to boiling and allowed to cool to about 35° C.D,L-methionine was added to arrive at a methionine moiety concentrationof about 2 mg/ml. Lactobionic acid was then added in an amount toachieve a concentration of about 2 mg/ml. Agatroban was then addedthereto in an amount sufficient to achieve a concentration of about 1mg/ml. The solution was packaged in appropriate containers as a ready-touse injectable and the completed packages were terminally heatsterilized.

Examples 15-16

Examples 12-13 are repeated except that in Examples 15-16, DL-methionineis added before the lactobionic acid.

Examples 17-22

Examples 11-13 are repeated except that in Examples 17-19, DL-methionineis added after the lactobionic acid, but before the argatroban; and inExamples 20-22, D,L-methionine is added after the argatroban, in each ofExamples 20-22 in an amount to result in a concentration of about 2mg/ml D,L-methionine, and in Examples 17-19 in an amount of about 10%greater than in Examples 20-22.

Example 23

11 mg of argatroban was dissolved in 2.6 ml of 0.025N sodium carbonateand the pH was adjusted with the addition of 1.5 ml of 0.025N HCl.Sufficient water for injection was added to bring the final solutionvolume to 10 ml, which had a pH of about 9.12.

Examples 24-25

11 mg of argatroban is dissolved in 5.5 ml of 0.025N sodium carbonate.In Example 24, 20 mg of D,L-methionine is added and then the pH isadjusted downward with 1.5 ml of 0.025N HCl. In Example 25, these twosteps are reversed. Water for injection is then added in a sufficientquantity to bring the final volume to 10 ml, which final solution has apH of about 8.85.

Example 26

Glycine was dissolved in water in an amount sufficient to achieve aglycine moiety final concentration of 2 mg/ml. The pH was then adjustedwith 1N sodium hydroxide to about 9.2. Sufficient argatroban was addedthereto to result in a final argatroban moiety concentration of about 1mg/ml. The final pH was adjusted, if needed, to about 9.2 with 1N sodiumhydroxide.

Examples 27-31

Example 26 is repeated except that lactobionic acid is added in anamount to result in a final lactobionic acid concentration of about 2mg/ml after the glycine is dissolved but before the pH is adjusted, andthe pH is adjusted to 8.5 (Example 27), 8.7 (Example 28), 9.0 (Example29), 9.5 (Example 30), or 10.0 (Example 31).

Examples 32A-32E

Ready-to-use formulations of argatroban for injection having thefollowing formulations are prepared having the following components:

Formulation Formula- Formula- Formula- Formula- Formula- Component tionA tion B tion C tion D tion E Argatroban 1 mg/ml 1 mg/ml 1 mg/ml 1 mg/ml1 mg/ml Lactobionic 2 mg/ml 2 mg/ml 2 mg/ml 2 mg/ml — Acid D,L- — 2mg/ml — 2 mg/ml — methionine Glycine 2 mg/ml — 2 mg/ml 2 mg/ml 2 mg/mlpH 9.2 8.7 8.7 8.7 9.5

Examples 33-35

Example 32A, C, D, and E is repeated is repeated except that the glycineis replaced by aspartic acid in Example 33, by glutamic acid in Example34, and by aminophthalic acid in Example 35.

1. A pharmaceutically acceptable formulation of argatroban of formula Ior a pharmaceutically acceptable salt thereof, which is solubilized inaqueous solution at a concentration greater than that of argatroban inwater alone, comprising (a) argatroban of formula I or apharmaceutically acceptable salt thereof; (b) methionine; (c)lactobionic acid, pharmaceutically acceptable salts, and mixturesthereof; and (d) an optional buffer; wherein the formulation has a pH inexcess of 8.5


2. The formulation of claim 1 which is (a) substantially free of ethanolor (b) substantially free of a mono-, di-, or oligo-saccharide andsubstantially free of a sugar alcohol.
 3. The formulation of claim 1 inwhich said argatroban is present in a concentration equivalent to anamount (based on the argatroban moiety) selected from the groupconsisting of about 1 mg/ml, about 1.25 mg/ml, about 2 mg/ml, about 2.5mg/ml or about 5 mg/ml.
 4. The formulation of claim 1 wherein saidbuffer is at least one member selected from the group consisting of atleast one of (1) a carboxylic acid, a hydroxy carboxylic acid, adicarboxylic acid, with at least of its acid group pK_(a)s greater than3.0, a salt thereof, or a mixture of said carboxylic acid and said saltthereof and (2) an alkali metal or ammonium carbonate, alkali metal orammonium bicarbonate, or mixtures thereof.
 5. The formulation of claim 1wherein said buffer is an acetate buffer, an amino acid buffer, oralkali metal or ammonium carbonate/bicarbonate buffer.
 6. Theformulation of claim 1 wherein said methionine is present in aft amountof about 1 mg/ml to about 50 mg/ml.
 7. The formulation of claim 1packaged in a vial selected from 5 mg/vial to 500 mg/vial or in an IVinfusion bag of a size selected from 25 ml/bag to about 500 ml/bag. 8.The argatroban formulation of claim 1 as a ready-to-administer aqueoussolution comprising (a) argatroban or a pharmaceutically acceptable saltthereof in an amount of at least 0.75 mg/ml (based on the argatrobanmoiety); (b)(1) lactobionic acid or a pharmaceutically acceptable saltthereof in an amount (based on the non-salt form thereof) or a mixtureof said lactobionic acid and lactobionic acid salt of at least 1.5 timesthe weight of the argatroban (based on the argatroban moiety) and/or(b)(2) an alkali metal or ammonium salt or mixture of alkali metal orammonium salts of carbonic acid or mixture of lactobionic acid salts inan amount based on CO₃ of at least 1.4 times the weight of theargatroban (based on the argatroban moiety); and (c) methionine or apharmaceutically acceptable salt thereof in an amount (based on thenon-salt form of methionine) of at least 1.5 times the weight of theargatroban (based on the argatroban moiety).
 9. The formulation of claim8 wherein said argatroban or pharmaceutically acceptable salt thereof ispresent in an amount of about 0.75 mg/ml to about 1.25 mg/ml based onthe argatroban moiety.
 10. The formulation of claim 8 wherein saidlactobionic acid or pharmaceutically acceptable salt thereof is present(based on the non-salt form thereof) in an amount of not more than 2.5times the weight of the argatroban (based on the argatroban moiety) orsaid alkali metal or ammonium salt or mixture of alkali metal orammonium salts of carbonic acid is present in an amount based on CO₃ ofnot more than 5.2 times the weight of the argatroban (based on theargatroban moiety).
 11. The formulation of claim 8 wherein saidmethionine or pharmaceutically acceptable salt thereof is present (basedon the non-salt form thereof) in an amount of not more than 2.5 timesthan weight of the argatroban (based on the argatroban moiety).
 12. Theformulation of claim 8 having a pH in excess of 8.6.
 13. The formulationof claim 8 having a pH of about 8.7, about 8.8, about 8.9, about 9.0,about 9.1, or about 9.2.
 14. The formulation of claim 8 having (1) aweight ratio of argatroban or pharmaceutically acceptable salt thereof:lactobionic acid or pharmaceutically acceptable salt thereof: methionineor pharmaceutically acceptable salt thereof (each based on therespective non-salt forms) of about 0.75 to about 1.25: about 1.50 toabout 2.50: about 1.50 to about 2.50 or (2) a weight ratio of argatrobanor pharmaceutically acceptable salt thereof: alkali metal or ammoniumsalt or mixture of alkali metal or ammonium salts of carbonic acid(based on methionine or pharmaceutically acceptable salt thereof (eachof the argatroban salt and amino acid salt based on the respectivenon-salt forms) of about 0.75 to about 1.25: about 1.4 to about 5.2:about 1.50 to about 2.50.
 15. The formulation of claim 8 having (1) aweight ratio of argatroban or pharmaceutically acceptable salt thereof:lactobionic acid or pharmaceutically acceptable salt thereof methionineor pharmaceutically acceptable salt thereof (each based on therespective non-salt forms) of about 1: about 2: about 2 or (2) a weightratio of argatroban or pharmaceutically acceptable salt thereof: alkalimetal or ammonium salt or mixture of alkali metal or ammonium salts ofcarbonic acid (based on CO₃) of about 1: about 1.9 to about 2.0: about 2or (3) a weight ratio of argatroban or pharmaceutically acceptable saltthereof: alkali metal or ammonium salt or mixture of alkali metal orammonium salts of carbonic acid (based on CO₃) of about 1: about 4.1 toabout 4.2: about
 2. 16. A reconstitutable formulation of argatrobancomprising (a) said argatroban or a salt thereof or mixtures thereof,(b) methionine or a salt thereof or mixtures thereof, (c) lactobionicacid or salt thereof or mixtures thereof, and (d) an alkali metal saltor ammonium salt of carbonic acid or mixtures thereof.
 17. A method ofreducing dosage administration errors in administering argatrobancomprising providing a pharmaceutically acceptable concentrateformulation or a ready-to-administer formulation of argatroban asdefined by the formulation of claim
 1. 18. A method of treatingthrombosis comprising administering to a patient having an argatrobantreatable condition the composition of claim
 1. 19. The method of claim18 where said composition is in a ready-to-administer form.
 20. Themethod of claim 18 where said composition is in the form of aconcentrate and diluting said concentrate with an injectably suitableaqueous diluent to a suitable concentration for injection.
 21. A methodof treating an argatroban treatable condition comprising administeringto a patient having an argatroban treatable condition a pharmaceuticallyacceptable formulation of argatroban of formula I or a pharmaceuticallyacceptable salt thereof, which is solubilized in aqueous solution,comprising (a) argatroban of formula I or a pharmaceutically acceptablesalt thereof, (b) methionine; (c) lactobionic acid; (d) a buffer; andhas a pH in excess of 8.5


22. The formulation of claim 1 which is (a) substantially free ofethanol and (b) substantially free of a mono-, di-, or oligo-saccharideand substantially free of a sugar alcohol.